The present invention is directed to a controlled release solid dosage form for biological components. In addition, the invention is directed to a method of delivery of beneficial microorganisms over an extended timeframe.
As a substance passes through the human gastrointestinal (GI) tract it is subjected to a wide range of pH values ranging from the neutral pH of the mouth, to the acidic conditions of the stomach, to the 5.0-7.5 pH range of the intestinal tract. Because the majority of biologically active components are highly pH sensitive, these changes in pH can cause significant effects upon the stability of the biological component and their ability to function in vivo. For example, many proteins denature in acidic environments; once denatured, their biological activity, if present, significantly differs from the non-denatured state. For a biological component (BC) to be functional, it must survive the gastrointestinal tract with minimal exposure to pH fluctuations. Further, BCs are also sensitive to enzymatic degradation. For example, one barrier to the oral administration of insulin is its susceptibility to enzymatic degradation.
The oral administration of biological components without a controlled release system has as a significant disadvantage not allowing for the biologic to by-pass the low pH and enzyme-rich environment of the stomach, thereby potentially decreasing the viability of the BC. For those devices which employ an enteric coating mechanism to survive the gastric environment, the shortcomings may be two-fold. First, the process of coating the dosage form or its contents may result in significantly lowered viability of the BC. Second, the downfall of merely by-passing the stomach is the explosive delivery of the biologic immediately upon exiting the stomach. This non-specific delivery is ineffectual and primitive in view of certain delivery needs of biological components because the bioavailability of BCs is often site dependent. Biological components may be targeted either through modification of the biologic itself or through the controlled release of the biologic within a desired physiologic window. One such biological component that displays such site-specificity is the lactic acid bacteria, Lactobacillus Acidophilus (a probiotic). L. Acidophilus is one example of other probiotics, including Lactobacillus bulgaricus, Lactobacillus casei subsp. Rhamnosus, Lactobacillus casei subsp. Casei, Lactobacillus salivarius, Lactobacillus brevis, Lactobacillus reuteri, Lactococcus lactis subsp. Lactis, Enterococcus faecium, Lactobacillus plantarum, Streptococcus thermophilus, Bifidobacterium infantis, Bifidobacterium Bifidum, Bifidobacterium longum, Saccharomyces boulardii, and various modified soil organisms.
Each strain of L. Acidophilus will attach at a different location of the intestinal tract, preferentially attaching within a region either slightly proximal or distal to other L. Acidophilus strains. These preferential regions of attachment are of particular importance relative to employing the bacteria as delivery systems for genomic or proteomic therapy, whether directly or as carriers for other vectors containing genetic or proteomic biologicals.
Beneficial microorganisms, for example, but not limited to, gastrointestinal flora such as lactic acid bacteria and yeast are an essential constituent of metabolism and immune response. Supplementation of beneficial microorganisms is a valid mechanism for replacement of flora lost due to antibiotic treatment, enhancement of naturally-occurring levels of beneficial flora, enhancing competitive inhibition and otherwise preventing enteropathogens, and altering the metabolism of ingested substances. Probiotics are one example of beneficial microorganisms.
Solid oral dosage forms employing controlled release have been increasingly demonstrated to be beneficial to the administration of pharmaceutical compounds, enhancing safety and consumer compliance, minimizing side effects and providing new therapeutic benefits. The four generalized platforms for controlled release solid oral dosage forms are diffusion, reservoir, pore-forming wax, or coated-bead systems. Few have been applied to BCs due to high development costs, bioavailability issues, and stability of the dosage BC within the dosage form. In the past, enteric coating technologies and other mechanisms of delayed release have been limited to features with explosive delivery after the stomach.
Controlled release delivery systems can take many forms including polymeric matrix systems, wax matrix systems, multi-particulate systems, and combinations thereof. The most commonly used delivery systems can be broadly classified as diffusion, reservoir, pore-forming wax, or coated-bead systems. Diffusion devices are composed of a drug dispensed in a polymer which diffuses from the entire physical tablet. Reservoir devices usually consists of a semi-permeable barrier which is involved in the release of the active from a core site within the tablet. Coated-bead systems employ an enteric or pH-sensitive coating of aggregated particles of the active ingredient packaged in capsule form. Pore-forming wax systems incorporate the active ingredient into a wax base and rely upon the rate of diffusion to control the release of the active ingredient.
In tableted, pore forming wax matrices, the BC and a water-soluble polymer are introduced into a wax or wax-like compound such as paraffin or guar gum, and then placed in an aqueous environment so as to allow the water-soluble polymer to dissolve out of the wax, resulting in the formation of pores. Upon contact with the gastrointestinal fluid, the pores facilitate diffusion-mediated release of the BC. The rate of release of the BC is dependent upon non-linear erosion.
Coated-bead systems are one of the few delivery systems available in both tablet and capsule form. The BC encased within a bead using one of the variety of processes available, such as spheronization-extrusion or coating of non-pareils. The coated-BC is then further coated with an enteric coating or employed in a blend of coated-beads with differing release rates for extended release formulations. The BC may also be blended or granulated with polymers before coating to provide an additional level of control. The coated-beads themselves may also be combined with polymers to create a hybrid diffusion or wax-based system. Coated-bead systems are complex to manufacture, requiring large numbers of excipients, use of solvents, and long manufacturing time. The use of such solvents and the manufacturing processes required to apply such solvents may expose the BC to adverse environmental conditions and cause a loss of the viability of the BC. This is especially concerning in the case of lyophilized BCs, where any exposure to moisture may cause significant decreases in viability.
An example of a reservoir system is the push-pull osmotic pump. These osmotically-controlled delivery systems feature a bi-layer tablet coated with a semi-permeable membrane possessing a laser-bored orifice through which the BC is pushed as aqueous solution is absorbed into the tablet. There are a number of osmotic delivery systems on the market that work via a similar physical principle; these osmotic systems produce very replicable, linear release. Manufacturing this system is definitively non-conventional, requiring specialized equipment and additional processing steps. The inherent complexity of the design adds a corresponding complexity to the development and scale-up of any osmotic membrane product.
The diffusion tablet systems rely on hydrophilic polymer swelling for control of BC release. Polymer systems can be sub-classified as conventional hydrogel systems and modified polymer systems. Conventional hydrogel systems rely upon the penetration of water to form of a gel-like phase through which the bioactive agent is released. These systems often incorporate the BC in a single polymer such as polyethylene oxide or hydroxypropyl methylcellulose. In the case of modified polymer systems, polymers with differing physical characteristics—such as one that is hydrophilic (e.g. HPMC), and one that is pH-dependent in its swelling characteristics, (e.g. pectin)—are combined with the BC. When these polymers interact with dissolution media, a transition phase or interfacial front develops, forming a gradually dissociating semi-solid core surrounded by a gel periphery that allows the BC to be increasingly released as the matrix hydrates. The movement of the dosage form through the gastrointestinal tract, through regions of increasing pH, permits further swelling and erosion of the matrix, culminating in complete release of the BC and complete dissolution of the dosage form.
Prior art formulations cannot deliver beneficial microorganisms over an extended time period or to targeted individual regions of GI tract. Prior art formulations require coating processes to achieve gastric bypass. Further, prior art formulations fail to provide mechanisms for pH control thereby rendering pH sensitive strains much less viable due to variations in GI pH. Further, prior art formulations lack mechanisms of isolating the BC from enzymatic degradation. Prior art formulations lack mechanisms to increase the stability of the dosage form itself through water sequestration of available water. Prior art formulations utilizing dietary fiber as a carrier require too large a volume for efficient oral dosage form manufacture. These and other limitations and problems of the past are solved by the present invention.